© Georg Thieme Verlag Stuttgart • New York – Synform 2016/09, A128–A130 • Published online: August 18, 2016 • DOI: 10.1055/s-0035-1562369

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SYNTHESIS Best Paper Award 2015: Harnessing the Intrinsic Reactivity within the Aplysinopsin Series for the Synthesis of Intricate Dimers: Natural from Start to Finish

Synthesis 2015, 47, 2367–2376

Background.Thieme Chemistry and the Editors of SYNTHESIS and SYNLETT present the ‘SYNTHESIS/ SYNLETT Best Paper Awards’. These annual awards honor the authors of the best original research papers in each of the journals, considering their immediate impact on the field of chemical synthesis.Erwan Poupon, Laurent Evanno and their co-workers from the Paris-Sud University (France) have won the inaugural SYNTHESIS Best Paper Award for the year 2015. The authors are recognized for their work on the synthesis of intricate dimers from aplysinopsin-type compounds. Paul Knochel, Editor-in-Chief of SYNTHESIS, remarked that the authors describe “in an elegant way how the consideration of biosynthetic aspects has led to the first total synthesis of dictazole B and its cyclobutane analogue. Their total synthesis of tubastrindole B has been achieved through a very original ring expansion starting from the dictazole precursor. In summary, a remarkable work clearly deserving the merits for best paper in 2015.”SYNFORM talked to Erwan Poupon and Laurent Evanno who were happy to share some background information regarding the prize-winning paper as well as their current research activities.

Biographical Sketches

Erwan Poupon is full professor of pharmacognosy and natural pro-duct chemistry at Paris-Sud Uni-versity, now part of Paris-Saclay University (France). He obtained his PharmD from the University of Rennes (France) in 1996 and his PhD from Paris-Descartes Uni-versity (France) in 2000 under the guidance of Professor Henri-Phi-lippe Husson. After a postdoctoral period in the group of Emmanuel

Theodorakis (University of California San Diego, USA), he join ed the faculty at Paris-Sud University. His scientific inter-ests include all aspects of natural product chemistry from their origin and evolution to their total synthesis.

Prof. E. Poupon

Laurent Evanno received his PhD degree in 2007 from the Pierre et Marie Curie University, Paris (France), working on total synthe-sis under the supervision of Dr. Bastien Nay at the ‘Muséum Natio-nal d’Histoire Naturelle’. He then undertook postdoctoral research with Professor Petri Pihko at Helsin-ki University of Technology – TKK (Finland) in 2008 and with Pro-fessor Janine Cossy at ESPCI–Paris

Tech (France) in 2009. Since 2010, he has been assistant pro-fessor at Paris-Sud University (France) and his research inter-ests encompass synthesis and isolation of natural substances especially in the field of indole alkaloids.

Dr. L. Evanno

Interview >

© Georg Thieme Verlag Stuttgart • New York – Synform 2016/09, A128–A130 • Published online: August 18, 2016 • DOI: 10.1055/s-0035-1562369

SYNTHESIS HighlightSynform

INTERVIEW

SYNFORM Could you highlight the value of your award-winning paper with respect to the state-of-the-art, potential or actual applications, and explain the origin, motivations and strategy used for conducting the research?

Prof. E. Poupon/Dr. L. Evanno We started the ‘aplysinop-sin project’ in early 2013 and we quickly wanted to evaluate the possibility of total syntheses with a high degree of atom economy in a limited number of synthetic steps with a sto-ryline deeply based on biosynthetic considerations. We nai-vely tried to dimerize an aplysinopsin-type starting material: we made numerous unsuccessful and frustrating attempts at this. Mehdi Beniddir (who was a post-doc in the team) made a fortuitous observation that opened the way out of the maze. Indeed, a sample of our starting material left on the bench in front of a window for several months had a slightly different appearance when compared to a freshly prepared batch. A routine LC-MS analysis of the sample indicated the presence of a small, intriguing new peak that could be a new dimeric compound. To be able to isolate the dimer, a sample was crus-

hed daily in a mortar and left directly under the sunlight for one month during August 2013. It was a great pleasure to iso-late and characterize a dictazole-type adduct for the first time. The design of a photochemical reactor efficiently mimicking sunlight (just as in a coral reef environment?) was a pressing need. Adam Skiredj, the PhD student involved in the project, brought us the solution through his passion for tropical frogs. Indeed, UV-enriched lamps made for terrariums were used to create sorts of ‘artificial lagoons’ in the lab mimicking thereby an intense sunlight exposure. To realize the synthesis of dic-tazole B (a cyclobutane-centered molecule), to achieve a ring expansion toward tubastrindole B (a tetrahydrocarba zole) and to rationalize the ‘aplysinopsin cascade’, the hard work of optimization had to be done. The project permitted access to these unusual densely-functionalized scaffolds starting only from creatinine, iodomethane and formylindoles as the sole, costless starting materials. Ongoing prospects of the project include an asymmetric version of the sequence. The project excited the whole team for several months, making our nights quite short, and we now feel honored that SYNTHESIS select-ed our article for the Best Paper Award 2015.

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Figure 1 Overview of the project (picture: copyright debitus/IRD)

© Georg Thieme Verlag Stuttgart • New York – Synform 2016/09, A128–A130 • Published online: August 18, 2016 • DOI: 10.1055/s-0035-1562369

SYNTHESIS HighlightSynform

SYNFORM What is the focus of your current research activity, both related to the award paper and in general?

Prof. E. Poupon/Dr. L. Evanno We are fascinated by natural substances, whatever their origin (plants, marine inverte-brates, insects, micro-organisms…). We are currently en gaged in multidisciplinary projects: discovering new molecules from nature, drug-design projects from natural product scaf-folds, answering chemical ecology issues… One of our main sources for reflection (and sometimes philosophical medita-tion) is trying to understand how molecular complexity is ge-nerated in nature and has emerged during evolution. For that, biomimetic strategies in total synthesis of complex molecules appear to us as not only a way to reach our synthetic targets, but also an ideal tool to dissect intimate mechanisms of bio-synthetic pathways. Our challenge is to find targets that may deploy impressive cascades of reactions from simple building blocks to afford complex skeletons: in that way the ‘aplysinop-sin project’ was ideal. A lesson we have learned in the last few years is that the simplest conditions are often the best in bio-mimetic strategies (no protecting group, room temperature, sunlight, air…).

SYNFORM What do you think about the modern role, major challenges and prospects of organic synthesis?

Prof. E. Poupon/Dr. L. Evanno Quite a difficult question to answer… let us put aside issues which are now consensual (environment-friendly chemistry, alternative carbon resour-ces) and focus more specifically on natural product chemistry and biomimetic approaches. Facing the ‘big data area’, we wish to try to transfer the huge body of knowledge, techniques and ways of thinking acquired in recent decades in genomics, proteomics and metabolomics to the field of organic synthe-sis. For this, routine analysis of complex mixtures, chemistry in confined media, supramolecular bio-inspired catalysis and many other tools will undoubtedly be fully integrated in hy-phenated projects in the coming years. Should our political and institutional leaders be conscious of the importance of fundamental and basic sciences, many discoveries, break-throughs and surprises, as well as much fun, are waiting for curious and motivated students. Also, as professors, education is essential for us especially at a period of sometimes re-emer-ging scientific obscurantism.

The award-winning team, from left: A. Skiredj, Prof. E. Poupon, Prof. D. Joseph, Dr. M. Beniddir, Dr. L. Evanno, Dr. G. Bernadat

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